Abstract
The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1–38) interacts differently with Aβ(1–40) and Aβ(1–42) and, in general, Aβ(1–38) interferes with the conversion of Aβ(1–42) to a β-sheet-rich aggregate. Functionally, Aβ(1–38) reverses the negative impact of Aβ(1–42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1–42) phenotype in Caenorhabditis elegans. Aβ(1–38) also reverses any loss of MTT conversion induced by Aβ(1–40) and Aβ(1–42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1–38) and Aβ(1–42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1–42)/Aβ(1–38) [and Aβ(1–42)/Aβ(1–40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1–38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1–42).
Highlights
The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides
Co-incubation with increasing concentrations of Aβ(1–38) progressively lessens the amount of high molecular weight (HMW) aggregate associated with 20 μM Aβ(1–42)
The AD brain tends to accumulate numerous Aβ species and we recently demonstrated that levels of insoluble Aβ peptides differed in a region- and sex-dependent manner in brain samples from autopsy-confirmed cases of A D27
Summary
The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. Shorter peptides, including Aβ(1–38) and Aβ(1–40), do not appear to exert any overt effect in this functional paradigm[21] and even with evidence that shorter variants, such as Aβ(1–38), might alter the fibrillogenic behaviour of Aβ(1–42) and provide some neuroprotection against Aβ(1–42) in cell culture[22], many Aβ length variants are still presumed to be neurotoxic or amyloidogenic. Motivated by these observations, we decided to re-evaluate the ‘amyloidogenic’ properties of Aβ(1–38), Aβ(1–40), and Aβ(1–42). Clinical relevance is suggested by the correlation between an earlier ageat-death and an increase in the soluble Aβ(1–42)/Aβ(1–38) ratio in cortical samples of males, but not females, with late-onset AD
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